Latent and Persistent Infections

Question 1

Characteristics of acute virus infection

Answer 1

Rapid onset of disease, relatively brief period of symptoms, results in elimination of either virus or host

Question 2

Acute virus replication is followed by…

Answer 2

Generation of a specific adaptive immune response that clears the pathogen and the establishment of immunological memory

Question 3

Overactive immune response can induce _______ _______

Answer 3

tissue damage

Question 4

Differences between acute and chronic infection

Answer 4

• Virus is not cleared (for months-to a lifetime)
• Initially robust immune response in subdued to prevent immunopathology while maintaing an adequate control of the virus activity
• The immune response of the host is set to a higher activation state overall

Question 5

Two types of viral life cycles during chronic infection:

Answer 5

Latent infection

Persistent replication

Question 6

Latent virus infection

Answer 6

A viral life cycle characterized by minimal (if any) expression of a subset of viral genes and absence of lytic replication and infectious virion production (Herpesvirus has both latent and lytic lifecycle)

Question 7

Herpesvirus lytic replication (12)

Answer 7

1. binding and fusion
2. Transport of DNA to the nucleus
3. Viral vhs degrades host mRNA
4. Viral transcription factor VP16 localizes to the nucleus to initiate transcription
5. Viral DNA circularizes
6. HSV alpha genes transcribed by host RNA polymerase II
7. Some alpha gene products transactivate transcription of beta genes
8. Some beta gene products are required for viral DNA synthesis
9. Viral DNA synthesis triggers expression of gamma viral genes
10. Many gamma gene products are structural components of virion
11. Viral DNA packaged into capsid
12. Filled viral capsid bud through host membranes

Question 8

What steps of infection are shared between lytic and latent lifecycle

Answer 8

Viral attachment and entry
Transport of DNA in the nucleus
Viral DNA circularizes and associates with host nucleosomes

Question 9

What happens to latent DNA after the inital steps of infection

Answer 9

Viral DNA is maintained y the cell as an extra chromosome - allows viral genome to survive cellular division

Question 10

Advantages of Latent virus infection

Answer 10

• Stealth - very few if any virus genes are expressed - invisible to immune response
• Virus relies on host cell mechanisms to maintain viral genome - difficult to target

Question 11

Disadvantages of latent virus infections

Answer 11

• Spread to naive is limited

- Death of a latently infected cell is a dead end for the virus

Question 12

How do latent viruses overcome the challenge of limited transmission to naive hosts?

Answer 12

Reactivation - switch from latent life cycle to lytic replication
- Very dangerous endeavor for virus - viral replication occurs in face of robust and highly virus specific adaptive immune response

Question 13

How do latent viruses overcome the challenge of infected cell death?

Answer 13

Viral latency is established in long lived cells
Herpesviruses: neurons, memory cells, stem cells
HIV: Memory T cells

Question 14

Chronic persistent virus infection

Answer 14

Virus is limited to a single life cycle: lytic replication
Lytic replication continues for the duration of chronic virus infection
T-cell exhaustion - constant stimulation prevents the development of a robust memory T-cell population

Question 15

T cell - exhaustion

Answer 15

T cells upregulate inhibitory receptors that attenuate signaling downstream of T cell receptor
This decreased TCR signaling eventually leads to loss of antiviral functions and death of T cells

Question 16

Steps of HIV infection

Answer 16

HIV enters the cell and releases RNA
Viral RNA is reverse transcribed into DNA which is integrated into host DNA
New viral RNA is used as genomic RNA and to make viral proteins

Question 17

HAART - highly active antiretroviral therapy

Answer 17

• HAART can lead to undetectable virus loads in the blood - but latently infected T cells can persist in the tissues
• Discontinuation of HAART in most cases will allow HIV reactivation and persistence
• Some of long-term non-progressors have control of HIV reactivation that is independent of HAART

Question 18

Latent chronic virus infection

Answer 18

• Infection is quiescent
• Reset the baseline of immune response by increasing systemic cytokine levels and decreasing activation threshold of immune system
• Disease is primarily generated by reactivation and/or expanded expression

Question 19

Overcoming pathogenesis of latent chronic virus infection

Answer 19

• Induce virus reactivation from latency with subsequent targeting of lytic virus processes
• Vaccine development is difficult because latency establishment efficient and independent of viral replication (in many cases)
• Prophylactic treatment of susceptible hosts with antivirals targeting lytic viral replication is a viable alternative

Question 20

Epstein Barr virus

Answer 20

We all have it (4 different programs of latent gene expression)

• Most have program 1 which has no effect on humans
• Other programs can lead to cancer

Question 21

Pathogenesis of persistent chronic virus infection

Answer 21

• Tissue and cellular damage associated with virus replication
• Tissue damage associated with inflammation and excessive immune response
• Chronic inflammation is associated with the development of cancer

Question 22

Overcoming pathogenesis of persistent chronic virus infection
Viral:
Host:

Answer 22

Viral: therapeutics that specifically target viral replication - administered as a combination and for a lifetime of infected individual
Host: mild immunosuppressive therapy can prevent tissue damage from host immune system - must be carefully balance to maintain virus specific immune responses